Abstract
BackgroundCell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 β (GSK3β) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin.Methodology and Principal FindingsWe show here that in conditions of serum starvation, the fibronectin receptor α5β1 integrin, but not α4β1, induced activation of GSK3β through Ser-9 dephosphorylation in adherent U937 cells. The GSK3β-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3β was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with α5 integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B' regulated the Ser-9 phosphorylation of GSK3β. In adherent leukemic cells, α5β1 integrin but not α4β1 upregulated the resistance to TNFα-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of α5β1 and GSK3β.Conclusions and SignificanceOur data show that, upon serum starvation, α5β1 integrin engagement could regulate specific pro-survival functions through the activation of GSK3β.
Highlights
The glycogen synthase kinase 3b (GSK3b) is a serine/threonine protein kinase that is involved in many physiological processes, playing important roles in glucose metabolism, cell cycle division, cell adhesion and apoptosis
glycogen synthase kinase 3 b (GSK3b), a4b1 and a5b1 integrins are implicated in cell survival of serum-starved adherent leukemic cells
Using a siRNA approach, we show that survival of adherent U937 on fibronectin in serumstarved conditions involves both GSK3b and b1 integrins (a4b1 and a5b1) (Fig. 1A)
Summary
The glycogen synthase kinase 3b (GSK3b) is a serine/threonine protein kinase that is involved in many physiological processes, playing important roles in glucose metabolism, cell cycle division, cell adhesion and apoptosis. At the post-translational level, the function of GSK3b is inhibited through phosphorylation of the Ser 9 residue by other protein kinases, including Akt, in response to insulin and growth factors [2]. Following integrin engagement, both inhibition and activation of GSK3b have been described. Cell adhesion to a 3D collagen matrix through a2b1 engagement promotes activation of GSK3b as well as protein phosphatase 2A (PP2A) [5]. We have recently demonstrated that the activation of glycogen synthase kinase 3 b (GSK3b) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin
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